The genes and their protein products involved in most human malignancies remain largely undefined. One approach to study such genetic loci has been to clone from human tumors segments of DNA containing specific chromosomal translocation cross-over points. The proposed work will use recently isolated DNA probes specific for t(14;18) translocations in B cell malignant lymphomas to characterize chromosome 18 encoded proto-oncogenes. Structural and sequence analyses already in progress of cDNA clones specific for one of these genes will continue. Since a major t(14;18) breakpoint cluster region maps within this transcriptional unit, one objective will be to determine the structural consequences of these translocations on proto-oncogene expression. Genomic DNA probes flanking a second t(14;18) breakpoint cluster region will be used as probes on Northern hybridizations to search for transcriptional products from a proposed gene nearby. Detected mRNA will be cloned as cDNA to carry out structural and sequence analyses. The genetic linkage and structural relatedness of the two breakpoint cluster regions will be determined by means of cDNA, phage and cosmid cloning. To investigate pathogenetic mechanisms of chromosome 18 breakage, sequence features of reciprocal t(14;18) translocation products will be determined. Sequence and/or restriction fragment length polymorphisms will be sought as markers for proposed constitutive fragile sites on chromosome 18. To explore the possible role of clonal Ig-pre-B cells in the development of biclonal lymphomas, chromosome 18 DNA rearrangements and V-J joints of light chain Ig genes will be determined for each subpopulation. Somatic mutations of tumor cell Ig genes will be used as chronologic markers to help define the contribution of host selective forces in the development and evolution of each subclone comprising a biclonal follicular lymphoma DNA probes for t(14;18) translocations will be used as clonal and prognostic markers to study various types of lymphoid disorders using genomic Southern blot hybridization. Comparisons will be made with various clinicopathologic parameters to determine possible prognostic correlations.